Abstract 310A: Transcription factors FOXP3 regulate ATF3 expression

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Abstract Activating transcription factor 3 (ATF3), a stress sensor, is rapidly induced by a variety of physiological and pathological signals, including those from cancer cells, and is essential in the complex processes of stress response. Several lines of evidence have demonstrated that ATF3 is involved in host defense and cancer development. Several studies also provide the relationship between ATF3 and p53 indicating that ATF3 binds to and stabilizes p53 while ATF3 is a negative regulator of TP53 gene expression. FOXP3, a well-known breast and prostate tumor suppressor, is a novel transcriptional repressor for several oncogenes including SKP2. However, whether ATF3 is the target protein of FOXP3 remains unknown. Herein, we demonstrate that ATF3 expression is regulated by FOXP3. First, we observed that overexpression of FOXP3 reduced ATF3 protein level in several cancer cell lines (H1299, HepG2, and Ishikawa cells). Secondly, FOXP3 dose-dependently reduced ATF3 promoter activity in gene reporter assay in several cell lines (MCF7, H1299, MDAMB231, and Saos2 cells). Since FOXP3 is regulated by post-translational modifications (PTMs), we next investigated whether PTMs affect FOXP3-mediated ATF3 expression. Interestingly, we observed that phosphorylation mutation on FOXP3 (Y342F) abolished FOXP3-mediated ATF3 expression. However, other PTM mutations on FOXP3, including S418 phosphorylation, K263 acetylation and ubiquitination, and K268 acetylation and ubiquitination, did not alter FOXP3-mediated ATF3 expression. Finally, FOXP3 binding site was found on ATF3 promoter region, around -870 bp region. Taken together, our results suggest that FOXP3 functions as a novel regulator of ATF3 and this novel event may be involved in tumor development and progression. Citation Format: Wei-Hsiung Yang, Chiung-Min Wang, William Yang. Transcription factors FOXP3 regulate ATF3 expression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 310A.